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Animal studies: a good guide for clinical trials? Study reveals animal experiments often fail to predict outcomes in humans.

December 14, 2006 -- Nature -- Animal-rights activists have long claimed that differences between humans and animals make experiments in species such as rats of little use. Most scientists disagree, saying that drug development would be impossible without initial tests in animals (see our Animal research special).

Now a team of medical researchers has published in the BMJ1 results from what they say is the first attempt to produce a scientific, quantitative answer to this question. The results provide food for thought for any scientist who works with animals.

The authors say they have highlighted serious problems with the way in which animal research is translated into human trials. Only half of the small sample of tests analysed by the team so far produced the same results in animals as they did in people.

The team stresses that this is not an argument against doing animal studies. Even so, the paper is likely to be seized on by activists.

The researchers started by taking six sets of clinical trials that had produced definitive answers as to whether specific treatments for conditions such as stroke and head injury are useful or not. They then assessed whether the prior animal research had given similar results to the human trials. The results, published today, say that the sets of data matched in only three of the six cases.

When the team investigated the reasons for this, they exposed a series of problems with the animal data. Many studies did not allocate animals randomly to control and treatment groups, a problem that is known to introduce bias into clinical trials. Comparison of experiments on a stroke treatment also suggested that studies showing negative effects are more likely to go unpublished, skewing impressions of efficacy.

Work on a model of head injury was undermined by the use of a model that did not match the later clinical trials. Rodents were injured and then treated five minutes later, says Ian Roberts, an author on the study and an epidemiologist at the London School of Hygiene and Tropical Medicine. In the clinical trials, which are based on hospital admissions, patients are typically treated within three hours of being injured.

Although the results could be seen as evidence that animal work does little to inform clinical studies, the authors stress that their results show only that more time needs to spent thinking about how to translate research between the two spheres. Better-designed models and an awareness of publication bias are two priorities, they say.

Other researchers question whether the results are really as alarming as they sound. Robert Lechler, an immunologist at Kings College London, says that designers of clinical trials are already well aware of limitations in animal models. He says that scientists apply an "intelligent filter" when looking at such tests, and that crude comparisons between the outcomes of animal and human studies do not capture this.

But Peter Sandercock, a neurologist at the University of Edinburgh and an author on the study, says the paper shows that more needs to be done on this front. If such a filter was applied, he points out, the animal models of head injury would have been repeated using a better design before human studies started. "This is not a polemic against animal research," stresses Sandercock. "But we need to be aware that there are biases in the animal trials."

My opinion is that a ratio of 1/2 is good. If half of the animal experiments translate into productive therapies for humans, this is a good thing. It beats dragging prisoners out of jail and using them instead of rats.

I don't know how to reconcile what the researchers found -- that half of the treatments showed similar results between human and animal tests -- and the fact that over the last 20 years or so, I believe only around 1 in 9 or 1 in 10 of all substances entering phase I trials actually make it through to become approved drugs. Every substance entering phase I trials would have shown positive results in animal testing, yet 85 - 90% of those substances don't pass all of the safety and efficacy requirements of the clinical trial process.

This subject has been on my mind for a while; recent postings that mention the animal model for MS prompt me to air my thoughts. Please bear with me as I vent.

Ever since Lyon posted the link to the MS brochure, "The History of MS," I have been troubled by the choice of the mouse model for MS:

Just before World War II, an important breakthrough occurred. An animal model of MS was developed out of research on vaccines. It had been known that people vaccinated against viral illnesses, especially rabies, sometimes developed a disease resembling MS

And then just two paragraphs later:

This laboratory animal form of MS, called experimental allergic encephalomyelitis, or EAE, would later become an important model for studying the immunology and treatment of MS. In fact, it paved the way to modern theories of autoimmunity, for it demonstrated how the body can generate an immunologic attack against itself.

"A disease RESEMBLING MS?" If scientists don't know the cause of MS, how do they know that EAE resembles it?!!! Lots of conditions RESEMBLE MS--how about the paresthesia of diabetic neuropathy? Many wind up in wheelchairs; many have disabilities; many RESEMBLE MS!!!

"It paved the way to the modern theories of AUTOIMMUNITY." Could research have taken a wrong turn in the road back then that kept us spending money, time, and effort on a dead-end? Many researchers (and laypeople like me) no longer think the answer is in autoimmunity.

Is it any wonder that work with this "model" does not always lead to something that WORKS in MS?

Whew! Thanks for offering me a place to vent. All of you understand, I'm sure, how the frustration builds and occasionally needs to be released.

"A disease RESEMBLING MS?" If scientists don't know the cause of MS, how do they know that EAE resembles it?!!! Lots of conditions RESEMBLE MS--how about the paresthesia of diabetic neuropathy? Many wind up in wheelchairs; many have disabilities; many RESEMBLE MS!!!

Although I agree that EAE is FAR from the best model for MS, what I think the scientists mean by "resemble" has to do with the myelin being stripped in the brain by the immune system. Whereas, if i am not mistaken, diabetic neuropathy is peripheral, under a different mechanism as well maybe. Under a microscope, EAE has the immune system attacking the myelin, which is what "they think" they see in MS autopsies?

Oh, Cure, I am in one of those "pits of frustration", I know. I wish I were smart, a scientist, able to understand everything. I wish someone would take our input seriously and explain what is known--in a book of thorough and easily understood language.

I feel I am looking in a thousand places for bits and pieces! I do not have a complete description of EAE, I have not read HOW it resembles MS.

As to your comment,

Under a microscope, EAE has the immune system attacking the myelin, which is what "they think" they see in MS autopsies?

researchers John Prineas and MH Barnett, right near you at the University of Sydney, found NO evidence of immune system involvement in autopsies they did on MS patients who had died of early, severe attacks. If EAE has immune involvement, but MS doesn't,...???

lyndacarol wrote:researchers John Prineas and MH Barnett, right near you at the University of Sydney, found NO evidence of immune system involvement in autopsies they did on MS patients who had died of early, severe attacks.

Yes, that has been the recent findings we all have read, but the EAE to MS connection was made long BEFORE any of these findings. Again, I am not happy with EAE, but I dont know of anything better either.

And from memory, these two docs actually work in the same building/organisation as my neuro. Maybe I should bring it up with my neuro on my next visit. On the last visit I forgot, and was running out of time. He is pretty hard to see. Maybe these guys take patients... hmmm.. a question to ask my refering doc.

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